Cystic Fibrosis Remedy Shows Promise in Tests on Mice

Boston researchers, in experiments with mice, have developed what they believe could be the first effective therapy for cystic fibrosis, a devastating genetic disease marked by life-threatening accumulations of mucus in the lungs and pancreas.

Human trials of the remedy, which involves administration of high levels of a purified form of a common food supplement, could begin early next year, they said Saturday at a Cystic Fibrosis Foundation conference in Seattle.

Using mice with the same genetic defect found in humans with the disease, researchers from Beth Israel Deaconess Medical Center found that cell membranes in the organs most affected by cystic fibrosis have a deficiency of a fatty acid called docosahexaenoic acid, or DHA.

Giving the animals large quantities of DHA dramatically eased disease symptoms, they reported. Because the mouse is considered such a good model for the disease, the results should hold in humans as well, the researchers said.

“This exciting research represents an entirely new strategy to correct and possibly even prevent some of the ravages of this disease,” said Robert J. Beall, president and CEO of the Cystic Fibrosis Foundation.

Although DHA is present in fish oils and nutritional supplements, the researchers warned strongly against patients taking such supplements on their own because other components could be harmful.

“If we were to leave patients with any message, it is ‘Don’t do it,’ ” Beall said. Cystic fibrosis victims who take high doses of the supplements “could do themselves irreparable harm” because of impurities in the commercial products, he added. “Give us the time to do clinical trials properly.”

Genzyme General of Cambridge, Mass., is now developing a suitable form of DHA for human testing that would eliminate such problems and is working as fast as possible to make it available, said Dr. David Meeker, Genzyme’s vice president for medical affairs. DHA is isolated from cold-water fish.

Cystic fibrosis, commonly called CF, is a genetic disease affecting about 30,000 children and adults in the United States, making it the most common fatal genetic disorder. About 1,000 new cases are diagnosed each year, most in early childhood.

CF causes cells lining the lungs and the pancreas to secrete an abnormally thick, sticky mucus. In the pancreas, the mucus blocks bile ducts used in secreting enzymes that help the body digest food. The mucus also clogs the lungs, impairing breathing and leading to a high incidence of life-threatening infections. About half of CF patients die before the age of 32.

The gene that causes CF was identified 10 years ago, and that discovery has led to many new approaches to treatment. Several gene therapy trials are now underway, for example, but none so far shows signs of great effectiveness.

At least 11 new treatments for CF are now in clinical trials. But if the new results reported in mice can be replicated in humans, DHA promises to be the most effective of all.

One particular advantage is that DHA would be taken orally to treat the whole body, while many of the other new treatments are directed only at the lungs or the pancreas, said Mary Lou McDowell, co-chairwoman of the National Cystic Fibrosis Awareness Committee.

Dr. Juan Alvarez and Dr. Steven Freedman of Beth Israel, a Harvard University teaching hospital, are specialists in studying the metabolism of fatty acids, the long molecules from which cellular membranes are constructed. Although other scientists have examined fatty acids in the bloodstream and found nothing unusual, Alvarez and Freedman decided to look at the tissues most affected by CF--the lungs, the pancreas and the intestine.

Using mice with the same genetic defect as humans, they found that those tissues had an unusually high level of a fatty acid called arachadonic acid, or AA, and unusually low levels of DHA. DHA, in particular, plays a key role in the functioning of cellular membranes, regulating the passage of materials into and out of the cell. Because the two fatty acids are linked in the cell, low levels of DHA lead to high levels of AA.

To see if this fatty acid imbalance was related to the disease, they fed a group of CF mice high levels of DHA for a week. After seven days, the AA/DHA ratio in the tissues had returned to normal and many of the symptoms were brought under control, Freedman said.

Bile ducts in the pancreas, for example, were no longer clogged or blocked. The intestines absorbed food better. And the lungs were no more susceptible to pneumonia than those of healthy mice. The researchers observed no side effects from the treatment, he added, and healthy mice given large doses of DHA showed no changes.

Working with researchers from the University of Massachusetts Medical Center, Alvarez and Freedman then studied biopsy tissues from the nose and colon of six humans with CF and six healthy controls. They found the same fatty acid imbalance in the human patients, but not in the controls.

“This lipid abnormality is truly a feature of CF,” Freedman said. That finding strongly suggests that the results in mice can be translated into humans.

DHA is a constituent of fish oil that is sold commercially as an aid for cholesterol control, as well as of some other food supplements. But Freedman cautioned against patients taking such products in high doses.

“Not only can we make animals much better with pure DHA, but we can also make them much sicker by giving them other fatty acids,” such as those found in the commercial products, he said. And eicosapentanoic acid, the primary constituent of fish oil, not only blocks the activity of DHA, but can suppress the growth of children who consume large quantities, he noted. The drug being developed by Genzyme would be pure DHA.

Information for patients, including a summary of the presentation and a Q&A;, can be found at the foundation’s Web site, https://www.cff.org.